Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors Journal Article


Authors: Mills, M. B.; Hudgins, L.; Balise, R. R.; Abramson, D. H.; Kleinerman, R. A.
Article Title: Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors
Abstract: Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline RB1 mutations. To further our understanding of the association of parental age and risk of de novo germline RB1 mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 Rb patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We classified Rb survivors into three groups: those with unilateral Rb were classified as sporadic if they had no or unknown family history of Rb, those with bilateral Rb were classified as having a de novo germline mutation if they had no or unknown family history of Rb, and those with unilateral or bilateral Rb, who had a family history of Rb, were classified as familial. We built two sets of nested logistic regression models to detect an increased odds of the de novo germline mutation classification related to older parental age compared to sporadic and familial Rb classifications. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and 5-year age increases adjusted for the age of the other parent. Mean maternal ages for survivors classified as having de novo germline mutations and sporadic Rb were similar (28.3 and 28.5, respectively) as were mean paternal ages (31.9 and 31.2, respectively), and all were significantly higher than the weighted general US population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted US general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of a survivor being in the de novo germline mutation group for each 5-year increase in paternal age, but these findings were not statistically significant (de novo vs. sporadic ORs 30-34 = 1.7 [0.7-4], ≥ 35 = 1.3 [0.5-3.3]; de novo vs. familial ORs 30-34 = 2.8 [1.0-8.4], ≥ 35 = 1.6 [0.6-4.6]). Our study suggests a weak paternal age effect for Rb resulting from de novo germline mutations consistent with the paternal origin of most of these mutations. © 2011 Springer-Verlag.
Keywords: adolescent; adult; child; preschool child; school child; child, preschool; retrospective studies; young adult; gene mutation; major clinical study; mutation; united states; genetic predisposition to disease; cohort studies; cohort analysis; genetic association; risk factors; retinoblastoma; retrospective study; cancer survivor; infant; infant, newborn; family history; interview; genetic risk; retinoblastoma protein; germ-line mutation; telephone; maternal age; genes, retinoblastoma; de novo germline mutation; paternal age
Journal Title: Human Genetics
Volume: 131
Issue: 7
ISSN: 0340-6717
Publisher: Springer  
Date Published: 2012-07-01
Start Page: 1115
End Page: 1122
Language: English
DOI: 10.1007/s00439-011-1126-2
PROVIDER: scopus
PUBMED: 22203219
PMCID: PMC3841976
DOI/URL:
Notes: --- - "Export Date: 1 August 2012" - "CODEN: HUGED" - "Source: Scopus"
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  1. David H Abramson
    326 Abramson